The nuclear hormone receptor superfamily of ligand activated transcription factors is present in various tissues, and responsible for a multitude of effects in these tissues.
The nuclear receptor (NR) superfamily presently comprises approximately 48 different proteins, most of which are believed to function as ligand activated transcription factors, exerting widely different biological responses by regulating gene expression. Members of this family include receptors for endogenous small, lipophilic molecules, such as steroid hormones, retinoids, vitamin D and thyroid hormone.
The nuclear receptor (NR) superfamily includes the steroid nuclear receptor subfamily, including the mineralocorticoid receptor (MR) (or aldosterone receptor), the estrogen receptors (ER), ER alpha (ER-α) and ER beta (ER-β), the androgen receptor (AR), the progesterone receptors (PR), glucocorticoid receptors (GR) and others. Also closely related in structure are the estrogen related receptors (ERRs) ERR-alpha, ERR-beta and ERR-gamma. The steroid nuclear receptors perform important functions in the body, some of which are related to the transcriptional homeostasis of electrolyte and water balance, growth, development and wound healing, fertility, stress responses, immunological function, and cognitive functioning. The effects may be mediated by cytosolic, mitochondrial or nuclear events. Accordingly, compounds that modulate (i.e. antagonize, agonize, partially antagonize, partially agonize) the activity of steroid nuclear receptors are important pharmaceutical agents that have specific utility in a number of methods, as well as for the treatment and prevention of a wide range of diseases and disorders modulated by the activity of steroid nuclear receptors. For instance, ER-β is present in, among other tissues, brain, bone, immune system, gastrointestinal tract, lung, ovary, endometrium, prostate, vasculature, urogenital tract, salivary gland, etc. The role of ER beta in these tissues was confirmed by observed phenotypes in ER beta knockout mice. Pathologies in these tissues may be treated by administration of ER-β selective ligands. ER-β in some cases functions as an antagonist of ER-α through heterodimerization with ER-α. For instance, agonists of ER-β may block the proliferative influence of ER-α in tissues such as prostate and breast where ER-α is known to promote neoplasia. In addition to its anti-ER-α mediated growth inhibition, ER-β autonomously inhibits proliferation and promotes differentiation of prostate and other cancers. ER-β is also believed to antagonize the proliferative effects AR in prostatic tissues. Prostatic hypertrophy and hyperplasia/dysplasia may result from a combination of androgenic stimulation of proliferation and/or failed activation of ER-β by locally synthesized estrogens. This hypertrophy or hyperplasia/dysplasia often leads to a variety of prostatic maladies such as BPH, prostatic inflammatory atropy (a precursor to neoplasia), PIN, and CaP. Administration of exogenous ER-β agonists can be expected to provide prostatic anti-proliferation thereby being beneficial in the prevention or treatment of these prostatic diseases. Additionally, decreased side effects can be expected for ER-β selective agents compared to isoform nonselective ligands for treating many of these diseases.
Non-lipid level dependent effects of estrogens on the vasculature are well known as evidenced by the cardioprotection conferred to pre-menopausal women by endogenous estrogen. Estrogens produce a direct vasodilatation (i.e. decreased vascular contractility or vascular tone) on a wide variety of vascular tissues which reduces systemic vascular resistance and improves microvascular circulation. Estrogens also reduce vascular cell proliferation and migration, vasoreactivity and hypertrophic remodeling, and vascular fibrosis. Although ER-α and ER-β are both thought to function in the vasculature, the deletion of ER-β as in knockout mice produces an elevation of blood pressure and moderate cardiac hypertrophy suggesting ER-β has a role in maintenance of vascular tone and proliferation. This cumulatively suggests that ER-β agonists may have therapeutic utility in hypertension, and a variety of other cardiovascular diseases such atherosclerosis and congestive heart failure. Some of the rapid effects of estrogens, particularly in the vasculature are believed to be independent of protein expression (i.e. nongenomic).
Members of the steroid nuclear receptor sub-family exhibit significant homology to each other and possess closely related DNA and ligand binding domains. Given the close similarity in ligand binding domains of the steroid nuclear receptors, it is not surprising that many naturally occurring and synthetic molecules possess the ability to modulate the activity of more than one steroid nuclear receptor.
In some embodiments of this invention, the NRBAs may also have anti-oxidant activity. Many of the processes that occur in vivo such as oxidative phosphorylation result in the production of a variety of reactive oxygen species (ROS) which are free radical and/or unstable molecules such as superoxide (O2−) and hydrogen peroxide (H2O2). These ROS react with a variety of endogenous macromolecules such as DNA, lipids, and proteins, oxidizing them and compromising their function. Over time this oxidative damage accumulates, producing or exacerbating various age-related pathologies. Nonlimiting examples include neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amytrophic lateral sclerosis, many types of cancer to include prostate and colon, vascular diseases such as stroke and various age-related dementias, and atherosclerosis, to name just a few oxidative stress related pathologies. Molecules such as ascorbic acid (Vitamin C), polyphenols such as derived from wine, and phytoestrogens such as genistein and coumestrol derived from soybean products have functional groups which can be oxidized by ROS. This chemical reaction returns the ROS to innocuous species such as oxygen (O2) and water, limiting the pathological damage inflicted to the cellular mileau. Additionally, ER-mediated anti-oxidant effects has been observed via induction of the expression of enzymes such as superoxide dismutase (SOD) and catalase that inactivate ROS. Hence, anti-oxidants are thought to exert an anti-aging influence when given on a regular basis. The combination of antioxidant, anti-inflammatory, and antiproliferative/pro-differentiation activities in the NRBAs of this invention may make them particularly potent chemopreventative agents for a variety of age-related diseases.